1,4,7,10-tetrahydro-1,7-dioxoquino(8,7-h)quinoline-3,9-dicarboxylate compounds

ABSTRACT

COMPOUNDS OF THE FORMULA   1,7-DI(O=),2,8-DI(Z-),3,9-DI(RO-CO-),5-Y,11-X-1,4,7,10-   TETRAHYDROQUINO(8,7-H)QUINOLINE   ARE USEFUL IN THE PROPHYLACTIC TREATMENT OF SENSITIZED HUMANS AND ANIMALS FOR ALLERGY AND ALL ANAPHYLACTIC REACTIONS OF A REAGIN OR NON-REAGIN MEDIATED NATURE. COMPOSITIONS OF THESE COMPOUNDS FORMULATED WITH PHARMACEUTICAL CARRIERS AND METHODS OF USING THESE COMPOSITIONS ARE ALSO PROVIDED.

United States Patent 3,838,132 1,4,7,10 TETRAHYDRO 1,7-DIOXOQUINO(8,7-h)QUINOLINE-Sfl-DICARBOXYLATE COMPOUNDS Charles M. Hall, 3835 Ruthin Road,Kalamazoo, Mich. 49002 No Drawing. Filed Sept. 8, 1972, Ser. No. 287,425Int. Cl. C07d 33/48 US. Cl. 260-286 R 7 Claims ABSTRACT OF THEDISCLOSURE Compounds of the formula are useful in the prophylactictreatment of sensitized humans and animals for allergy and allanaphylactic reactions of a reagin or non-reagin mediated nature.

Compositions of these compounds formulated With pharmaceutical carriersand methods of using these compositions are also provided.

BRIEF SUMMARY OF THE INVENTION This invention relates to novel compoundsof Formula Ia, pharmaceutical compositions employing these compounds,and a process for the prophylactic treatment of allergic conditions insensitized mammals using these compounds.

- DETAILED DESCRIPTION OF THE INVENTION In accordance with thisinvention there are provided compounds represented by Structure Ia3,838,132 Patented Sept. 24, 1974 wherein it is understood that Ia canexist in its tautomeric form Ib and that the compounds of this inventionare likely to be mixtures of all tautomeric forms, the percentages ofeach tautomer to be at least partially dependent on the nature of R, X,Y, and Z and the physical environment of the compound.

0 C-OR N Z Y I on no I z N 0R Ib For the purpose of brevity throughoutthe application and appended claims, the compounds will be referred tohereinafter in their keto form, structure Ia.

The R substituent is selected from the group consisting of hydrogen,alkyl from one to three carbon atoms, inclusive; phenyl, and apharmaceutically acceptable metal or an amine cation.

Z is selected from the group consisting of hydrogen, alkyl from one tothree carbon atoms, inclusive; and phenyl.

X and Y can be the same or different monosubstituents. When X and Y aredifferent monosubstituents, one monosubstituent must be hydrogen and theother monosubstituent is selected from the group consisting of alkylfrom one to three carbon atoms, inclusive; alkoxy from one to threecarbon atoms, inclusive; phenyl; halogen; hydroxy; nitro;trifluoromethyl; cyano; amino; carboxyamide; and

where Q is selected from the group consisting of hydrogen; alkyl fromone to three carbon atoms, inclusive; phenyl; and a pharmaceuticallyacceptable metal or amine cation, with the proviso that where R is alkylfrom one to three carbon atoms, inclusive; or phenyl; then Q is an alkylfrom one to three carbon atoms, inclusive; phenyl, hydrogen, or apharmaceutically acceptable metal or amine cation, and where R ishydrogen or a pharmaceutically acceptable metal or amine cation, then Qis the same as R. When X and Y are the same monosubstituent, they areselected from the group consisting of hydrogen, chlorine, bromine, andmethoxy.

The preferred compounds are those compounds where R is selected from thegroup consisting of hydrogen or a pharmaceutically acceptable metal oramine cation. Z is hydrogen. X and Y can be the same or differentmonosubstituents. When X and Y are difierent monosubstituents, onemonosubstituent is hydrogen and the other monosubstituent is selectedfrom the group consisting of alkyl from one to three carbon atoms,inclusive; alkoxy from one to three carbon atoms, inclusive; halogen;cyano; and

where Q is selected from the group consisting of hydrogen and apharmaceutically acceptable metal or amine cation and is the same as R.When X and Y are the same monosubstituent, they are selected from thegroup consisting of hydrogen, chlorine, bromine, and methoxy.

The more preferred compounds are those compounds where R is selectedfrom the group consisting of amine 5 cations. Z is hydrogen. X and Y canbe the same or different monosubstituents. When X and C are differentmonosubstituents, one monosubstituent is hydrogen and the othermonosubstituent is selected from the group consisting of alkyl from oneto three carbon atoms, inclusive; alkoxy from one to three carbon atoms,inclusive; halogen; and cyano. When X and Y are the samemonosubstituent, they are selected from the group consisting ofhydrogen, chlorine, bromine, and methoxy.

As employed in the above disclosure and throughout the specification,the term halogen includes fluoro, chloro, bromo, and iodo and the termalkyl includes methyl, ethyl, propyl, and isopropyl when limited tothree carbon atoms. The term a pharmaceutically acceptable metal oramine cation includes alkali metals such as sodium and potassium,alkaline earth metals such as calcium and magnesium, other acceptablemetals such as aluminum, and amine cations. The term amine cationincludes all pharmaceutically acceptable amine cations, including, i forexample, cations of ammonia, tris(hydroxymethyl) aminomethane, D-threo 2amino-1-p-nitrophenyl-1,3- propanediol, N,N-bis(hydroxyethyl)piperazine, 2-amino- 2-methyl 1 propanol, 2-amino 2 methyl1,3-v propanediol and 2,2-bis(hydroxymethyl)-2,2', 2"-nitriolotriethanoland further amines including H NR, HNR' and NR';,, wherein R is selectedfrom the group consisting of alkyl from one to three carbon atoms,inclusive, .and CH CH OH.

The compounds of this invention can be prepared by methods known to theart. The basic synthetic pathway employed is the reaction of anappropriately substituted naphthalene 1,5 diamine (II) with anoxaloacetate sodium salt (III) in the presence of a solvent to form thediadduct (IV). The R group is limited to an alkyl of from one to threecarbon atoms, inclusive; and phenyl. Ring 0 closure to the desiredcompound (la) is accomplished by heating the diadduct at appropriateconditions.

sY IIIZIHQ 0 0 Z O Roo-h-l J-h-lL-mz 7 Na NHz X II III Y N C-Z 5:0

C N-El Z C X After the synthesis has been carried out, the carboxylatecan be transesterified to other esters or hydrolyzed to the carboxyacid. The carboxy acid is converted to metal or amine salts by standardmethods.

It should be noted that because of the symmetry of the compounds of thisinvention, a monosubstituent at the 5 position is equivalent to amonosubstituent at the 11 position.

The starting materials of the synthesis, X and Y substituted naphthalene1,5 diamine compounds where X and Y are the same or different, have beenprepared in the art. Examples of these compounds include naphthalene 1,5diamine, 4.8 dibromonaphthalene 1,5 diamine, 4,8 dimethoxynaphthalene1,5 diamine, 4- methylnaphthalene-1,5-diamine, and 4 nitronaphthalene-1,5-diamine.

X and Y substituted 1,5-dinitronaphthalene compounds where X and Y arethe same or different have also been prepared in the art. Examples ofthese compounds include 4,8 dichloro 1,5 dinitronaphthalene,4-chloro-1,5-dinitronaphthalene, and 4-arnino-1,5-dinitronaphthalene.

Compounds with various substituents at the X and Y position and includedwithin the scope of the invention can be conveniently prepared by goingthrough a diazotization of the 4-amino 1,5 dinitronaphthalene startingmaterial, placing the appropriate X substituent at the 4 position, andthen reducing the dinitro compound to the diamino compound with theappropriate X or Y substituent in place, the reduction effected bytreatment with hydrogen and a palladium charcoal catalyst or with ironand hydrochloric acid in ethanol.

For example, 4-amino 1,5 dinitronaphthalene is diazotized with nitrousacid formed in situ by sodium nitrite and hydrochloric acid. Thediazonium salt is then contacted with potassium cyanide to form4-cyano-l,5- dinitronaphthalene. The 4-cyano compound can be reduced tothe 1,5-diamine by either of the processes disclosed above or hydrolyzedwith water to 4-carboxy1,5- dinitronaphthalene which can be esterifiedto any of the carboxy esters of this invention or, alternatively, the 4-carboxy 1,5 dinitronaphthalene compound is converted to 4trifiuoromethyl 1,5 dinitronaphthalene with sulfur tetrafluoride. The 4trifiuoromethyl 1,5 dinitronaphthalene can be contacted withdimethylcadmium to form the 4-acetyl 1,5 dinitro compound which is thendiazotized with nitrous acid formed in situ and contacted with sodiumhydroxide, thereby forming the 4-hydroxy- 1,5-dinitronaphthalenecompound. The 4hydroxy is then conveniently converted to the 4-alkoxy1,5 dinitronaphthalene compound by acylation with an appropriatealkylhalide.

The above reactions for synthesizing starting materials of thisapplication are carried out by standard methods known to the art. Oncethe appropriate X or Y substituent is in place, the dinitro grouping canbe reduced to the diamine by one of the disclosed methods and thecompounds of the invention prepared by the synthetic pathway previouslyoutlined.

The second reactant, the oxaloacetate derivative is also readilyavailable. Compounds where R is ethyl and Z is hydrogen, methyl, ethylor phenyl are known in the art.

Where Z is hydrogen, an alternative reagent to the oxaloacetatederivative is available to form the diadduct. Acetylene dicarboxylate(V), where R is limited to alkyl of from one to three carbon atoms,inclusive; or phenyl, can be added to the substitutednaphthalene-1,5-diamine to form the diadduct (IV), where Z is hydrogenas illustrated below:

Y IIIHz In the formation of the diadduct and subsequent ring closure,the following processing conditions can be observed.

When using the oxaloacetate reagent to form the diadduct, there shouldbe a suflicient amount of acid present to protonate the oxaloacetatecarbanion and catalyze the removal of the keto grouping. The acid canalso serve as a solvent for the two reagents as well. For example,glacial acetic acid, propionic acid, p-toluene sulfonic acid, andbutyric acid are acids which can be used. If a further reagent is neededto place the two reactants into solution (or a co-solvent desired),benzene, toluene, diethylether, dioxane, tetrahydrofuran, or alcoholsfrom one to about four carbon atoms can be employed. The length of timefor the formation of the diadduct is temperature depend ent. At roomtemperature the reaction proceeds rather slowly but as the temperatureis raised, reaction time is decreased. Acceptable reaction times areachieved at temperatures ranging from about 40 to about 70 C., althoughreaction temperatures can be above 100 C. if desired.

With regard to the use of the acetylene dicarboxylate reactant in theformation of the diadduct, appropriate solvents are alcohols having fromone to about six carbon I atoms, preferably one to about three carbonatoms, benpromoted by an increase in temperature to about 100 C.

Ring closure of the diadduct, prepared by the methods disclosed above,and formation of the desired compound can be accomplished by heating thediadduct at a relatively high temperature. This heating can be done tothe neat diadduct. However, it is preferred to use a solvent which canfunction as a heat transfer medium. Any high boiling inert solvent suchas a mineral oil, hexamethylphosphoric triamide, diphenyl ether, orDowtherm A, which appears to be primarily diphenyl ether, is suitable.The ring cyclization step is preferably carried out at temperatures offrom about 220 C. to about 280 C., although lower .or highertemperatures can be employed if desired. Particularly preferred solventsare Dowtherm A, or diphenyl ether, which boil at about 250 0, thusenabling the ring cyclization to occur during reflux.

An additional advantage of the elevated temperature during the ringcyclization step is that any adduct formed in the preceding step which inot in a position to cyclize since it is trans to the benzene ring isisomerized to the cis configuration during the heating, thereby allowingsubstantial yields of the desired compound to be produced. This transadduct preparation occurs more frequently when an aprotic solvent andacetylene dicarboxylate are used in the adduct formation step. As statedpreviously, at this point various esters, the acid, or salts can beprepared at the R position of the carboxy group. Different esters can beprepared by a standard transesterification then Q is the same as R.

Following is an illustrative list of starting materials and desiredcompounds which can be prepared bythe above disclosed procedures:

TABLE II Starting material Y IIIHz o z 0 nob-ii-iion where Z=H NHz XProduct X Y R H H CH3 F H CzHs Br H CaH7 I H iC H1 CHa H CaHs CzHs H CH3CaH7 E 02115 1C3H1 E 03111 002115 H CaHfi OCaHv H CH3 OIC3H7 H CzHs C 3H CaH1 H iCaH' COOH H CGHE COOCgHs H CH3 TABLE III The aboveillustrative examples of Table II are'prepared where Z in theoxaloacetate sodium salt is methyl, ethyl, propyl, isopropyl, or phenyl.

TABLE IV The illustrative examples of Tables 11 and III are converted tocompounds where R is hydrogen or a pharmaceutically acceptable metaloramine cation suchas those exemplified earlier.

For reason of brevity, Tables III and IV'are not rendered in the samemanner as Table II, but the same illustrative scoping is intended.

The following examples are compounds in accordance with this invention.The compounds are intended not'to limit but merely to exemplify theinvention.

7 EXAMPLE 1 Dimethyl 1,4,7,l-Tetrahydro-1,7-dioxoquino[8,7-h]quinoline-3 ,9-dicarboxylate a. Tetramethyl2,2'-(1,5-naphthalenediimino)-dibutenedioate.30 Gram of dimethylacetylenedicarboxylate was added slowly to a solution of 15.8 gram of1,5-naphthalenediamine in 250 ml. of methanol. The mixture is stirred atroom temperature for six hours, during which time the yellow product, a1:2 adduct, precipitates and is collected by filtration.Recrystallization gives a yellow solid melting at 220 C.

Analysis.Calcd. fol CgzHggNgOaZ C, 59.72, H, N, 6.33. Found: C, 59.43,H, 5.00, N, 6.40.

The UV, IR, and NMR spectra are in agreement with the structure.

b. Product.5.0 gram of the 1:2 adduct is added to refluxing Dowtherrn A,boiling point about 250, and the mixture is heated at the refluxtemperature for five minutes. The reaction mixture is cooled and theyellow crystalline product collected by filtration. The melting point isgreater than 310 C.

EXAMPLE 2 Disodium 1,4,7,IO-tetrahydro-l,7-dioxoquino[8,7-h]quinoline-3,9-dicarboxylate 1.0 gram of the diester prepared in Example1 is heated in 50 ml. of 1.0N NaOH for thirty minutes. The mixture iscooled, diluted with water, and methanol added. The precipitate isfiltered and collected.

EXAMPLE 3 1,4,7, 1 0-Tetrahydro-1,7-dioxoquino [8,7-h] quinoline- 3,9-dicarb oxylic acid To the cooled, diluted mixture of Example 2 isadded suflicient acid to adjust the pH to 3. The desired diacidprecipitates and is collected by filtration. The melting point isgreater than 310 C.

EXAMPLE 4 Di Tris(hydroxymethyl)methylammonium l,4,7,10 tetrahydro 1,7dioxoquino [8,7 h] quinoline 3,9 dicarboxylate The diacid prepared inExample 3 is dissolved in an equivalent of aqueous tn's(hydroxymethyl)aminomethane. Methanol is added to the solution and theprecipitate is collected.

The compositions of the present invention are presented foradministration to humans and animals in unit dosage forms, such astablets, capsules, pills, powders, granules, sterile parenteralsolutions or suspensions, and oral solutions or suspenions, andoil-in-water and water-in-oil emulsions containing suitable quantitiesof the compound of Formula Ia. The preferred method of administration isby inhalation into the lung by means of an aerosol liquid or powder forinsufflation. Another preferred route of administration with thesecompounds, particularly where R is tris(hydroxymethyDmethylammonium andZ is hydrogen, is oral.

For oral administration either solid or fluid unit dosage forms can beprepared. For preparing solid compositions such as tablets, the compoundof Formula Ia is mixed with conventional ingredients such as talc,magnesium stearate, dicalcium phosphate, magnesium aluminum silicate,calcium sulfate, starch, lactose, acacia, methylcellulose, andfunctionally similar materials as pharmaceutical diluents or carriers.Capsules are prepared by mixing the compound with an inertpharmaceutical diluent and filling the mixture into a hard gelatincapsule of appropriate size. Soft gelatin capsules are prepared bymachine encapsulation of a slurry of the compound with an acceptablevegetable oil, light liquid petrolatum or other inert oil.

Fluid dosage forms for oral administration such as syrups, elixirs, andsuspensions can be prepared. The water-soluble forms can be dissolved inan aqueous vehicle together with sugar, aromatic flavoring agents andpreservatives to form a syrup. An elixir is prepared by using ahydro-alcoholic (ethanol) vehicle with suitable sweeteners such as sugarand saccharin, together with an aromatic flavoring agent.

Suspensions can be prepared with an aqueous vehicle with the aid of asuspending agent such as acacia, tragacanth, methylcellulose and thelike.

For parenteral administration, fluid dosage forms are prepared utilizingthe compound and a sterile vehicle, water being preferred. The compound,depending on the vehicle and concentration used, can be either suspendedor dissolved in the vehicle. In preparing solutions the compound can bedissolved in water for injection and filter sterilized before fillinginto a suitable vial or ampul and sealing. Advantageously, adjuvantssuch as a local anesthetic, preservative and buffering agents can bedissolved in the vehicle. To enhance the stability, the composition canbe frozen after filling into the vial and the water removed undervacuum. The dry lyophilized powder is then sealed in the vial and anaccompanying vial of water for injection is supplied to reconstitute theliquid prior to use. Parenteral suspensions are prepared insubstantially the same manner except that the compound is suspended inthe vehicle instead of being dissolved and sterilization cannot beaccomplished by filtration. The compound can be sterilized by exposureto ethylene oxide before suspending in the sterile vehicle.Advantageously, a surfactant or wetting agent is included in thecomposition to facilitate uniform distribution of the compound.

Additionally, a rectal suppository can be employed to deliver the activecompound. This dosage form is of particular interest Where the mammalcannot be treated conveniently by means of other dosage forms, such asorally or insufilation, as in the case of young children or debilitatedpersons. The active compound can be incorporated into any of the knownsuppository bases by methods known in the art. Examples of such basesinclude cocoa butter, polyethylene glycols (Carbowaxes), polyethylenesorbitan monostearate, and mixtures of these with other compatiblematerials to modify the melting point of dissolution rate. These rectalsuppositories can weigh from about 1 to 2.5 gm.

The preferred compositions are those adapted for inhalation into thelung and containing a compound of the invention which is water-soluble.For treatment of allergic conditions of the nose, such as rhinitis,compositions adapted for contact with nasal linings are preferred.

Compositions for inhalation are of three basic types: (1) a powdermixture preferably micropulverized; (2) an aqueous solution to besprayed with a nebulizer; and (3) an aerosol with volatile propellant ina pressurized container.

The powders are quite simply prepared by mixing a compound of theformula with a solid base which is compatible with lung tissue,preferably lactose. The powders are packaged in a device adapted to emita measured amount of powder when inhaled through the mouth.

Aqueous solutions are prepared by dissolving the compound of the Formulala in water and adding salt to provide an isotonic solution andbuffering to a pH compatible with inhalation. The solutions aredispersed in a spray device or nebulizer and sprayed into the mouthwhile inhaling.

Aerosols are prepared by dissolving a compound of the Formula Ia inwater or ethanol and mixing with a volatile propellant and placing in apressurized container having a metering valve to release a predeterminedamount of material.

The liquefied propellant employed is one which has a boiling point below65 F. at atmospheric pressure. For use in compositions intended toproduce aerosols for under the trademarks Freon and Genetron. Mixturesof the above-mentioned propellants may suitably be employed. Examples ofthese propellants are dichlorodifluoromethane (Freon 1'2),dichlorotetrafluoroethane (Freon 114), trichloromonofluoromethane (Freon1'1), dichloromonofluoromethane (Freon 21), monochlorodifluoromethane(Freon 22), trichlorotrifluoroethane (Freon 113), difiuoroethane 142-A)and monochlorotrifiuoromethane (Freon 13).

The term unit dosage form, as used in the specification and-claims,refers to physically discrete units suitable as unitary dosages forhuman subjects and animals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect in association with the required pharmaceutical.diluent, carrier or vehicle. The specifications for the novel unitdosage forms of this invention are dictated by and directly dependent on(a) the unique characteristics of the active material and the particulareffect to be achieved and (b) the limitations inherent in the art ofcompounding such an active material for use in humans and animals, asdisclosed in detail in this specification, these being features of thepresent invention. Examples of suitable unit dosage forms in accord withthis invention are tablets, capsules, pills, suppositories, powderpackets, wafers, granules, cachets, teaspoonfuls, tablespoonfuls,dropperfuls, ampuls, vials, aerosols with metered discharges, segregatedmultiples of any of the foregoing, and other forms as herein described.

An effective but non-toxic quantity of the compound is employed intreatment. The dosage of the compound for treatment depends on the routeof administration. A dosage schedule of from about 0.01 to about 10 mg.of compound in a single dose administered parenterally or by inhalationin the compositions of this invention is effective for preventingallergy attacks. More specifically, the single dose is from about 0.05to about 1 mg. of compound. The oral and rectal dose is from about 0.1to about 20 mg. in a single dose. More specifically, the single dose isfrom about 0.1 to about 5 mg. of compound. The dosage to be administeredcan be repeated up to four times daily. However, when it is necessary torepeat treatment, a preferred dosage schedule reduces the secondarytreatment dosage to from about 0.5 percent to about 20 percent of theabove dosages, more specifically, from about 1 to about percent of theabove dosages. In this manner, a state of allergy prophylaxis can bemaintained. The reduced'dosage is taken until that dosage no longerprovides effective protection. At that time, the larger dosage isrepeated, followed by the reduced dosage. An example of such a dosageschedule is the following: An asthmatic individual insufilates 0.05

mg. of the tris(hydroxymethyl)aminomethane salt of 1,4,7,10-tetrahydro-l,7 dioxoquino[8,7h]quinoline 3,9-dicarboxylic acid.Four hours later the individual insufliates 0.0005 mg. of the samecompound and every four to six hours thereafter insuffiates 0.0005 mg.of the same compound until effective asthma prophylaxis is not provided.The individual then insufliates 0.05 mg. of the same compound, thenreduces the insufilation dosage to 0.0005

(Genetron ing ingredients:

10v vidual comes into contact with substances (antigens) to which he isvallergic, will prevent the allergic reaction which would otherwiseoccur.

EXAMPLE 5 A lot of 10,000 tablets, each containing 1 mg. of dimethyl1,4,7,l0 tetrahydro 1,7 dioxoquino[8,7-h]- quinoline-3,9-dicarboxylateis prepared from the following types and amounts of incredients:

The compound and dicalcium phosphate are mixed well, granulated with 7.5percent solution of methylcellulose in water, passed through a No. 8screen and dried carefully. The dried granules are passed through a No.12 screen, mixed thoroughly with the talc, starch and. magnesiumstearate, and compressed into tablets.

These tablets are useful in preventing hay fever attacks at a dose of 1tablet every four to six hours.

EXAMPLE '6 One thousand two-piece hard gelatin capsules, each containing1 mg. of disodium 1,4,7,10 tetrahydro-1,7-dioxoquino[8,7-h] quinoline3,9-carboxylate are prepared from the following types and amounts ofingredients:

Disodiu-m 1,4,7,10 tetrahydro 1,7 dioxoquino [8,7-h1-quinoline 3,9dicarboxylate 1 Talc 150 Magnesium stearate 1 The ingredients are mixedwell and filled into capsules of the proper size.

Capsules so prepared are useful in preventing attacks of bronchialasthma at a dose of one capsule every four to six hours.

EXAMPLE 7 One thousand tablets, each containing 1 mg. of dimethyl1,4,7,10 tetrahydro 1,7 dioxoquino[8,7-h] quinoline-3,9-dicarboxylateare prepared from the following types and amounts of ingredients:

Dimethyl 1,4,7,10 tetrahydro 1,7 dioxoquino [8,7-h]quinoline 3,9carboxylate 1 Microcrystalline cellulose NF 420 Starch Magnesiumstearate powder 5 The ingredients are screened and blended together andpressed into 526 mg. tablets.

The tablets are useful to protect against food allergy at a dose of 1tablet before meals.

EXAMPLE 8 A sterile preparation suitable for intramuscular injection andcontaining 0.1 mg. of disodium 1,4,7,l0-tetrahydro 1,7dioxoquino[8,7-h]quinoline 3,9 dicarboxylate in each milliliter isprepared from the follow- Disodium 1,4,7,10 tetrahydro 1,7 dioxoquinoOne milliliter of this sterile preparation is injected for prophylactictreatment of allergic rhinitis.

1 1 EXAMPLE 9 Six hundred ml. of an aqueous solution containing 0.1 mg.of tris(hydroxymethyl)aminomethane salt of 1, 4,7,10-tetrahydro 1,7dioxoquino[8,7-h]quinoline-3,9- carboxylic acid per ml. is prepared asfollows:

Tris(hydroxymethyl) aminomethane salt of 1,4,7,

IO-tetrahydro 1,7 dioxoquino[8,7-h]quinoline- 3,9 dicarboxylic acid mg.60 Sodium chloride gm. 0.6 Water for injection q.s ml. 600

The THAM salt and sodium chloride are dissolved in sufficient water tomake 600 ml. and sterile filtered.

The solution is placed in nebulizers designed to deliver 0.25 ml. ofsolution per spray.

The solution is inhaled into the lungs every four to six hours forprevention of asthmatic attacks.

EXAMPLE 10 A powder mixture consisting of 5 mg. oftris(hydroxymethyl)aminomethane salt of 1,4,7,10 tetrahydro 1,7-dioxoquino[8,7-h]quinoline 3,9 dicarboxylic acid and sufficient lactoseto make 5 grams of mixture is micropulverized and placed in aninsuffiator designed to deliver 50 mg. of powder per dose.

The powder is inhaled into the lungs every four to six hours forprevention of asthma attacks.

The powder is inhaled into a nostril of the nose every four to six hoursfor prevention of rhinitis.

EXAMPLE 1 1 Twelve grams of an aerosol composition are prepared from thefollowing ingredients:

Gm. Tris(hydroxymethyl)aminomethane salt of 1,4,7,

IO-tetrahydro 1,7-dioxoquino 8,7-h] quinoline- 3,9 dicarboxylic acid0.025 Freon 12 1.440

Freon 114 2.160

Water 7.775 Sorbitan monoleate 0.600

The THAM salt is dissolved in the water and combined with the otherconstituents under pressure. The twelve grams of composition are addedto a 13 cc. plastic coated bottle and capped with a metering valve. Themetering valve releases 80 mg. of composition in an aerosol. The aerosolis inhaled every four to six hours for prevention of asthmatic attacks.

EXAMPLE 12 In individuals who require continual treatment in theExamples 5 through 11, the dosage of the Example is given initially andeach succeeding administration of the drug is at 5 of the initialdosage. This maintenance dosing is continued until effective allergyprophylaxis is not obtained. The initial dosage of Examples through 11is then started once more, followed by the maintenance dosages.

EXAMPLE 13 the following manner:

Female Sprague-Dawley 250 gm, rats are skin-sensitized with ratanti-ovalbumin homocytotropic antibody that is heat labile and has apassive cutaneous anaphylaxis titer of 1:128. After a 72-hour latencyperiod, the animals are challenged iv. with 4 mg. Ovalbumin. (0A) +5 mg.Evans blue dye and the test compound. Thirty minutes later theextravascular bluing that results from antigen antibody combination atthe skin site is read. Antibody dilutions are used such that in controlanimals a 4 mm. spot is the lowest detectable spot, and 4 or 5 lowerdilutions are used to give a range of antibody in each animal. Four tofive animals are used for each variable in the experiment. Percentinhibition of the PCA assay is calculated by comparing the spot scoresof treated rats with the spot scores of control rats. The spot score isthe total number of detectable spots over the number of animals.

The tris(hydroxymethyl)aminomethane salt of 1,4,7,10 tetrahydro 1,7dioxoquino[8,7-h]quinoline 3,9 dicarboxylic acid is prepared bydissolving the dicarboxylic acid in an equivalent weight of aqueoustris(hydroxymethyl)aminomethane and is tested in the rat passivecutaneous anaphylaxis assay in the above manner.

The inhibitory dose for the tris(hydroxymethyl)- aminornethane salt of1,4,7,10 tetrahydro 1,7 dioxoquino[8,7-h]quinoline-3,9 dicarboxylicacid, when given i.v., is 0.005 mg./kg.

What is claimed is:

1. A compound of the formula wherein R is selected from the groupconsisting of hydrogen, alkyl from one to three carbon atoms, inclusive;phenyl, and a pharmaceutically acceptable and compatible with the anionutility metal or amine cation;

Z is selected from the group consisting of hydrogen, alkyl from one tothree carbon atoms, inclusive; and phenyl;

X and Y are the same or different monosubstituents and when X and Y aredifferent monosubstituents, one monosubstituent is hydrogen and theother monosubstituent is selected from the group consisting of alkylfrom one to three carbon atoms, inclusive; alkoxy from one to threecarbon atoms, inclusive; phenyl; halogen; hydroxy; nitro;trifluoromethyl; cyano; amino; carboxyamide; and

O -O Q,

where Q is selected from the group consisting of hydrogen, alkyl fromone to three carbon atoms, inclusive; phenyl and pharmaceuticallyacceptable and compatible with the anion utility metal or amine cationwith the proviso that where R is hydrogen or a pharmaceuticallyacceptable and compatible with the anion utility metal or amine cation,then Q is the same as R; and

when X and Y are the same monosubstituent, they are selected from thegroup consisting of hydrogen, chlorine, bromine, and methoxy.

2. A compound in accordance with Claim 1 wherein R is selected from thegroup consisting of hydrogen or a pharmaceutically acceptable andcompatible with the anion utility metal or amine cation;

Z is hydrogen;

X and Y are the same or different monosubstituents and when X and Y aredifferent monosubstituents, one monosubstituent is hydrogen and theother monosubstituent is selected from the group consisting of alkylfrom one to three carbon atoms, inclusive; alkoxy from one to threecarbon atoms, inclusive; halogen; cyano; and

where Q is selected from the group consisting of hydrogen and apharmaceutically acceptable and compatible with the anion utility metalor amine cation and is the same as R; and

when X and Y are the same monosubstituent, they are selected from thegroup consisting of hydrogen, chlorine, bromine, and methoxy.

3. A compound in accordance with Claim 1 wherein R is a pharmaceuticallyacceptable and compatible with the anion utility amine cation;

Z is hydrogen;

X and Y are the same or different monosubstituents and when X and Y aredifferent monosubstituents, one monosubstituent is hydrogen and theother mono- References Cited FOREIGN PATENTS 2,145,423 9/1971 Germany260287 DONALD G. DAUS, Primary Examiner M. C. VAUGHN, Assistant ExaminerUS. Cl. X.R.

260-289 R, 268 R, 288 R, 270 R, 283 CN, 283 SY; 424258, 250

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTIONPATENT NO. 3,838,132 DATED September 24, 1974 INVENTOR(S) CharIes M.HaII It is certified that error appears in the above-identified patentand that said Letters Patent is hereby corrected as shown below:

Column 3, I1'ne 7; change "and C are" to --and Y are--.

Column 4, Iine 8; change "4.8-" to --4,8- I CoIumn 6, h'ne 45; change tot OH 0R CoIumn 7, h'ne 55; change "suspenions" to "suspensions".

CoIumn 12, Iine 67; change "and pharmaceuticaIIy" to --and apharmaceuticaIIy-- Signed and Scaled this Twenty-ninth Day of July 1980[SEAL] Arrest:

SIDNEY A. DIAMOND Arresting Ojficer Commissioner of Patents endTrademarks

